British Journal of Haematology, 2001, 112, 282±292
Historical Review
LEUKAEMIA ± A BRIEF HISTORICAL REVIEW FROM ANCIENT TIMES TO 1950
`The longer you can look back ± the further you can look
forward': Winston Churchill in an address to The Royal
College of Physicians, London 1944. At the time that
Churchill was speaking in 1944, leukaemia was a fatal
disease that had been identified 100 years before. The
disease was described as the dreaded leukaemias, sinister
and poorly understood.
Looking back
From ancient times, the spleen had been described in
anatomical detail, as were the features of anaemia, malaria
and some infectious diseases. Most of these are associated
with spleen enlargement (Isaacs, 1937). The literature to
ad 500 revealed no evidence of blood malignancies,
notwithstanding that the common term `cancer' was used
by Galen (c. ad 130±200) (Mettler, 1947). The first report
of haemophilia recognized by circumcision (Rosner, 1937)
came from the Babylon Talmud (completed c. ad 500).
The Egyptians, the Greeks and the Romans had not
produced the means of magnification, therefore microscopic
examination of the blood was not possible until much later.
Robert Hooke, Curator of The Royal Society of London,
published the first major work devoted to microscopy which
advanced biological studies (Hooke, 1665). The outstanding
pioneering microscopist was Anton van Leeuwenhoek, born
in Delft in 1632, whose skill in grinding lenses led to the
development of a number of primitive compound microscopes. He described human red blood cells (van Leeuwenhoek, 1674) and there is little doubt that this was the first
time that they had been described and identified.
The white cells, `the globuli albicantes', were first noted
by Joseph Lieutaud (1703±80) (Lieutaud, 1749), the
French anatomist, some 20 years before William Hewson
(1739±74), anatomist and a Fellow of The Royal Society,
published his major work on the lymphatic system and first
described the lymphocyte (Hewson, 1774).
Early in the nineteenth century, a small number of cases
of patients with uncommon or peculiar alterations of the
blood was published (Table I), but the scant evidence
provided in the publications was insufficient, seen in
retrospect, to support a definite diagnosis of leukaemia.
Pus corpuscles had already been described as being colourless and nucleated ± the `globules blancs du pus' (de Senac,
1749), and physicians accepted that pus and inflammation
were associated with the blood. The question of how the
Correspondence: Gordon J. Piller, Abbotswold, Great Wolford,
Shipston on Stour, Warwickshire CV36 5NQ, UK.
282
blood came to be altered in colour was a matter which was
yet to be addressed. It was understandable that in the
decades before leukaemia was identified any major changes
noted in the colour of the blood would be interpreted as an
indication of pus in the blood.
Of the cases in Table I, two might suggest symptoms of
chronic leukaemia: Dr Barth's patient (1839), whose blood
was examined the day after death by Alfred DonneÂ, a French
physician and a pioneering microscopist who was one of the
first to teach the clinical use of the microscope, and Dr David
Craigie's patient of 1841. DonneÂ's report on the blood of
Barth's patient was:
`More than half of the cells were mucous globules. This
fact needs perhaps some explanation. You know that
normal blood contains three types of cells (i) red cells ±
the essential cellular constituent of the blood (2) white cells
or mucous cells (which I consider as being secreted from the
vascular wall) (3) the small globules. It is the second variety
which dominates so much that one wonders, knowing
nothing about the clinical course, whether this blood does
not contain pus. As you know the pus cell cannot yet be
differentiated with definite accuracy from mucous cells.'
(DonneÂ, 1844)
Donne included this and Rayner's case in his collected
lectures on microscopy published in 1844.
It was Craigie, an Edinburgh physician, who, although
not a microscopist or an histologist, tenaciously questioned
the clinical features of a patient admitted to the Royal
Infirmary in 1841. He was puzzled and unable to interpret
what he observed. His patient died after presenting with
some of the clinical symptoms of chronic leukaemia, and the
blood examined after death by the hospital pathologist
showed that the purulent matter and lymph had been mixed
with the blood and had been circulated (Craigie, 1845).
Craigie resolved to keep a look-out for any similar cases
admitted to the hospital.
Pus and inflammation continued to dominate haematological thought until the middle of the nineteenth century,
and the understanding of the meaning of pus was the
subject of many disputes. Looking back, there was nothing
in the literature to reveal any clinical cases which might be
suggestive of a diagnosis of leukaemia before the nineteenth
century.
Three years later, John Menteith, aged 28, was admitted
to the Edinburgh Royal Infirmary, presenting with a splenic
tumour and other symptoms similar to Craigie's patient of
1841. Treatment consisted of the application of leeches,
purgatives and potassium iodide. Menteith improved and
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Table I. Some known cases from the available literature on cases of uncommon or peculiar alteration of the blood before the identification of
leukaemia as a disease.
Date
Physician/surgeon
Patient
Age
Place
Reference
1811
1827
1829
1833
1839
P. Cullen
A. Velpeau
M. Collineau
M. A. Duplay
Barth
Rayner
D. Craigie
Thomas Halke
Female
Male
Josephine GueÂvis
Housewife
Male
Peter Campbell
35
63
29
27
44
?
30
Skegness
Paris
Paris
Paris
Paris
Paris
Edinburgh
Cullen (1811)
Velpeau (1827)
Collineau et al (1829)
Duplay (1834)
Dreyfus (1957)
Donne (1844)
Craigie (1845)
1841
was discharged, only to be readmitted 3 months later.
Craigie had no doubts that the `internal pathological state'
must be the same in both patients and that it would have
the same termination. It did, 3 days later on 15 March 1845.
With the approval of Professor Christison, to whose ward
the patient was admitted, John Hughes Bennett (Fig 1),
then at the age of 33 a lecturer in clinical medicine and
pathologist at the Royal Infirmary Edinburgh, carried out
the post mortem. Bennett had attended the lectures on
clinical microscopy given by Alfred Donne in Paris and
supported DonneÂ's perseverance in overcoming the antagonism of the profession to the use of the microscope as a
clinical instrument (Dreyfus, 1957). The detailed report
prepared by Bennett, dated 19 March 1845, was published
in the Edinburgh Medical and Surgical Journal 1 October 1845
and was entitled `Case of Hypertrophy of the Spleen and
Liver in which Death took place from Suppuration of the
Blood' (Bennett, 1845). This was a turning point.
The identification of leukaemia
Bennett's paper stated that what he observed in the blood
was entirely opposed to all that was then known of pus and
inflammation. He concluded that the alteration of the blood
in the case of John Menteith was independent of inflammation and that transformation had taken place throughout
the system. The whole mass of blood had been affected.
By microscopic examination, he saw round corpuscles of
various sizes and when he applied acetic acid to the cells a
distinct nucleus appeared. He wrote, `This nucleus was
generally composed of one large granule ¼ but here and
there two or three smaller granules' (Bennett, 1845). His
drawings of these cells were published (Bennett, 1852) and
were the first illustrations of the blood cells of a patient with
leukaemia (Fig 2). The symptoms described in the clinical
notes together with the extensive post mortem report would
today be diagnosed as chronic granulocytic leukaemia.
The disease might well have been first observed by DonneÂ,
whose findings were not published until l855 (DonneÂ,
1855), but Bennett's paper gave leukaemia its first
published recognition as a clinical entity.
The second case of leukaemia was reported by Rudolf
Virchow (Fig 3), then aged 24 years and a demonstrator
in pathological anatomy at the Charite Hospital in Berlin.
His patient, Marie Straide (aged 50), was admitted to the
hospital in March 1845 with a 4-year history of ill health
and a swollen lower abdomen. Four months later, she died
and Virchow performed the post mortem on l August 1845.
He too found `everywhere in the vessels a mass thoroughly
resembling pus' and also reported cell nuclei in various
shapes. He added that the proportions between coloured and
colourless blood corpuscles were approximately the reverse
of those in normal blood, nominally in the ratio of about
`300 red cells to one white' (Virchow, 1845). Virchow was
describing a case of chronic lymphocytic leukaemia. His
publication, entitled Weisses Blut, was published in November 1845, 6 weeks after Bennett's paper. There was a
Fig 1. John Hughes Bennett (1812±75) in 1847 (portrait by
Bosse, University of Edinburgh).
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Fig 2. The microscopic appearance of
blood as seen by J. H. Bennett, Edinburgh.
similarity between Virchow's and Bennett's findings,
although the latter's report was more detailed. A year
later, Virchow amended his first description of white blood
to explain that the colourless cells were of varying size and
shape, as had already been pointed out by Bennett. Virchow
(1847) reported a similar case, and for the first time used
the name `leukhemia' (white blood) to describe this newly
observed disease. This was not a new name. White blood
had been described as early as 1729 by Dr Beal and again by
Dr Lower in 1749 (Lowthorp, 1749). Bennett preferred the
more exact title of leucocythaemia, or white cell blood.
Virchow's third case was published in 1849, again involving
a patient with hypertrophy of the spleen. He concluded that
there were two types of the disease ± the splenic and the
lymphatic forms ± distinguished by the starting site of the
disease (Virchow, 1849).
Dr Henry Fuller, a physician at St George's Hospital in
London, reported a case which was most probably chronic
granulocytic leukaemia (Fuller, 1846). Fuller examined this
patient's blood three times under the microscope and once
again after death; on each occasion, he found a large
proportion of abnormal, granular colourless globules. This
was the first recorded use of the microscope to diagnose
leukaemia in a living patient.
Fuller reported another case (Fuller, 1850) which is of
particular historical interest. A 9-year-old girl presented at
St. George's Hospital in February 1850 and was treated as
an outpatient, but died 2 months later. In the case history,
Fuller stated that she had enjoyed tolerable health until July
of the previous year, and he noted that the time from the
onset of ill health to death was 8 months. His diagnosis was
leucocythaemia. Bennett was interested in this case and
asked Fuller for further details of the patient's illness. It was
revealed that the child had frequent haemorrhage, her
gums were spongy, her spleen very enlarged and the blood
picture showed `a large number of colourless granular,
spheroidal globules varying in size'. Fuller's detailed notes
made it possible for the findings to be put independently by
the author to three experts for a professional view on the
diagnosis (Piller, 1992). Their judgement on Fuller's case
was that it was an unusual case of childhood leukaemia, not
typical of its acute form but of chronic myeloid leukaemia.
This may therefore be the first recorded case of childhood
leukaemia. Fuller's observation is most important because
at that time children were expressly barred from hospitals in
the belief that they were carriers of infection. Leukaemia
Fig 3. Rudolf Virchow (1821±1902). Photograph from the late
1850s.
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285
Fig 4. Testimonial from Rudolf Virchow in
support of John Hughes Bennett. (From the
unpublished bound volumes of original
documents held in the Special Collections of
the University of Edinburgh library.)
was identified at a time when, in London, of the 50 000
deaths recorded (Registrar General's Report, 1846) 21 000
were of children under the age of 10 years. Cholera,
typhoid, typhus fevers, tuberculosis, diphtheria, gasteroenteritis, rickets and malnutrition were the scourges of the
time.
In 1852, Bennett, who had become Professor of the
Institutes of Medicine in the University of Edinburgh,
published the first data collection of 35 cases of leukaemia
or cases which might suggest leukaemia (Bennett, 1852).
This demonstrated a wider geographical distribution of the
disease. Further proof of this came later that year, when
Professor G. B. Wood of Philadelphia called the attention of
its College of Physicians `to a form of the disease described
by Dr Bennett of Edinburgh', thus reporting the first case of
leukaemia in America. The diagnosis was supported by
Addinell Hewson, then a pathologist in Philadelphia and a
grandson of William Hewson.
Controversy and priority
Both Bennett and Virchow, in recognizing leukaemia as a
separate and distinct disease and by evaluating their clinical
findings, had emancipated the colourless corpuscles from
the dominance of the so-called pus corpuscles. Their work
also marked the recognition that white cells possessed
different types of nuclei. Neither of them could explain the
mechanisms, the sources or the cause of the new disease.
Both then went on to pursue and further their other
interests. They were in some respects similar in ambition,
intelligence and in their achievements, and the records
show they enjoyed a mutual respect. It was others who
spread ill-conceived reports of quarrels between the two
men and initiated debates in journals on their findings.
Controversy ensued from 1854 on the naming of the new
disease and on the priority of its discovery. KoÈlliker (1854)
wrote the history of the discovery of leucocythaemia as it
was understood in Germany. He advanced the claim of
Virchow. Bennett replied in a paper in the same journal and
defended his position (Bennett, 1854). This so-called dispute
between Bennett and Virchow was repeated by others well
into the last century, mostly by those who had not examined
the facts or, indeed, did not have the will to do so. The
question of priority was resolved publicly by Virchow in a
lecture that he delivered in 1858, in which he stated, `It is
the same conclusion which Bennett came to in the muchdiscussed matter of priority between us when he observed a
case of indubitable leukaemia some months before I saw my
first case' (Virchow, 1858a±c). Virchow, KoÈlliker and Vogel
all wrote enthusiastic testimonials in support of Bennett's
candidature for two chairs in Edinburgh, the chair in the
Institutes of Medicine in 1848 (Fig 4) and the chair of the
Practice of Physic in 1855. It is improbable that they would
have responded so warmly if there was no mutual respect.
Bennett was well known in European medical circles; he
had spent 4 postgraduate study years in France and
Germany and was fluent in both languages.
It was not just the principals who were being criticised
but also the disease. A lengthy debate conducted by some of
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the leading physicians in France and lasting six consecutive
meetings was held in Paris in 1855±6 (SocieÂte MeÂdicale des
Hopitaux de Paris, 1864). The debate centred upon whether
leukaemia was in fact a separate disease. The arguments
acquired a fervently factional character. Some thought it
was a cachexia following chronic conditions, others that it
was a special form of malaria and the majority of members
sheltered behind traditional medicine, which demanded that
it was first necessary to collect `pathological observations
for a long time in order that by cautious analysis the
cause of the excess of white cells and its significance
could be determined'. Those who supported the autonomy
of leukaemia were in the minority, but Gabriel Andral,
professor of general pathology and therapy at the University
of Paris and a staff member of the HoÃpital de la ChariteÂ,
proposed the study of the blood as a clinical discipline
and with Piorry, his contemporary, defended the use of
the microscope in clinical medicine. Leukaemia gradually
became accepted as a distinct disease and published case
reports grew in number. Clinical and pathological descriptions of the disease became more detailed, but so too did
speculation on its causes. The definition of leukaemia
was far from precise and not all the reports could be
substantiated as being clinically correct.
A third classification was introduced in 1857 by Nikolaus
Friedreich, a pathologist in Wurzburg. He reported at length
on a case which he described as acute leukaemia, the first
time the term was used. His patient, aged 46, presented
6 weeks before her death (Friedreich, 1857). The colourless
cells that he observed in mass at the top of the thorax were
the leucocytes in their now known various types performing
their defensive role. (The functions of these cells were not
established until James Gowans's work a century later.) The
short time between presentation and death and the disease's
rapid development made Friedreich sure that this was a case
of acute leukaemia of the lymphatic type.
Scientific developments applied to leukaemia
A vital discovery came in 1868 when Ernst Neumann,
Professor of Pathological Anatomy at Konigsberg, reported
changes in the bone marrow in leukaemia and established
the link between the source of blood and the bone marrow.
His lifelong work was on the study of haemopoiesis and
blood pigments. The pathway of this meticulous research
was developed from the search for the origin of the red cells
and led to his two fundamental discoveries ± that the
marrow is the source of blood formation and that it is a
continuous process. His preliminary communication in
1868 was followed a year later by a publication of the
extensive description of cells in the marrow (Neumann,
1869). A year later, he announced that the red cells in the
circulating blood were derived from an ancestral cell
(Neumann, 1870). Around the same time, Giulio Bizzozero,
a 22-year-old medical graduate of Pavia, published two
articles confirming the observation that non-nucleated red
blood cells were formed from nucleated red cells in the
marrow and that the blood formation function of the bone
marrow also included white blood cells (Bizzozero, 1868,
1869). His scientific interests were varied, but after his work
on the function of the marrow he concentrated on the
mechanism of coagulation and identified the platelet
(Bizzozero, 1882). Neumann's work on the bone marrow
continued, and after two further papers he stated in 1872
that leukaemia was a disease of the marrow (Neumann,
1872). Six years later, he added the classification myelogenous leukaemia to the splenic and lymphatic types of the
disease (Neumann, 1878).
The findings of Neumann and Bizzozero were not
universally accepted, particularly in view of the latter's
youth and inexperience. Many divergent theories were
circulated at that time and acceptance of the new site of
haemopoiesis and the origin of the red cells was slow in
developing. Claude Bernard, as President of the French
Academy of Science, recognized the great achievements of
Neumann and Bizzozero, and the French haematologist
Jolly deplored the unfortunate influence of Hayem (Jolly,
1907), who accused Neumann and Bizzozero of encumbering science by ill-formed statements (Hayem, 1889) that did
not permit the discoveries to be accepted universally for
nearly 20 years. For some years, the mystery remained of
how the cells were able to travel through the bone to the
circulatory blood system. Bone was seen as a solid mass,
and this gave support to the views of those who looked with
suspicion upon the discoveries.
The next significant step forward came in 1877 when
Paul Ehrlich, while still a medical student, developed a
triacid stain which for the first time provided a clear
definition of the nucleus, the cytoplasm and other details of
the blood cells in a thin dried film (Ehrlich, 1877). With the
much-improved compound microscope, his development of
methods of staining slides to differentiate between types of
blood cells began a new era in medicine and gave rise to a
pathway of new specialities in pathology. Ehrlich worked
with analine dyes which were classified according to their
chemical affinities and he introduced the names acidophil
(later changed to eosinophil because of the cell's affinity to
eosin), basophil and neutrophil for the three different
granulocyte types of white blood cells (Ehrlich, 1880).
This new advance simplified the classification of leukaemia
into two varieties, the myeloid group (granulocytes) of cells
from the bone marrow and the lymphoid group (lymphocytes) of non-granular cells. As a consequence, the term
splenic leukaemia was no longer considered to be a type of
the disease but an organ affected by it. Ehrlich identified the
primitive cell, which he described as a cell in a semitransformed state being an ancestor cell from which other cells
were developed within the distinct cell lineages. This was
probably the first time that an ancestral cell in the
haematopoietic series had been described, the earliest use
of the concept of the stem cell. Ehrlich maintained that
leukaemia was a primary disease of the haemopoietic
system (Ehrlich, 1887) and his techniques initiated the
morphological era of haematology.
In 1900, the Swiss haematologist Naegeli made an
important discovery which supported Ehrlich's view that
the various cell lineages were distinct (Naegeli, 1900). He
described a new cell in the myeloid cell line, which he
named the myeloblast, and he showed this to be an ancestor
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of granulocyte cells. He also showed the lymphoblast as
the cell in the lymphoid cell line responsible for the
lymphocytes. Naegeli claimed that there was a recognizable
distinction between the two ancestor cells. From then, the
presence of primitive myeloblasts and lymphoblasts in
the circulating blood formed a classic diagnosis of
acute leukaemia. Monocytic leukaemia was first described
by Reschad & Schilling-Torgau (1913) and others, but
Naegeli's review concluded that the monocytes were
unusual forms of myeloblasts. Naegeli's view was subsequently declared incorrect and it was acknowledged that a
rare type of leukaemia occurs in which the blood picture is
predominantly monocytic.
Towards the end of the nineteenth century, the source
of the blood had been described, the means of identifying
blood cells and some of the immediate precursors had
been discovered and basic cell lineage had been discussed. A
clearer definition of the classification of the subtypes of
leukaemia had also been established, but these scientific
advancements were of little consequence in the treatment of
the disease. There was still a lack of any form of effective
therapy in the treatment of leukaemia. Alfred Carpenter, a
consultant physician in Croydon who read a paper on
leucocythaemia to the Medical Society of London in 1880,
expressed the clinical frustrations, `There was something
wanting in the present plan of dealing with therapeutics in
as much as members of the medical profession are
continually trying processes for the cure of diseases which
have been shown to be useless, and the textbooks continue
to recommend medicines which have never done any good'
(Carpenter, 1880).
Early therapy
Leukaemia was generally accepted as being a chronic
disease and the limited therapeutics in the armoury of the
physician were applied. For example, quinine was used for
fever, morphine and opium for diarrhoea and pain, iron
for anaemia, iodine for external use as an antibacterial and
arsenic was also used. Arsenic had already been used
therapeutically when in 1786 Thomas Fowler, a physician
in York, introduced a 1% solution of arsenic trioxide
(Fowler's solution) for the cure of agues, remittent fevers
and headaches. The first report of the use of arsenic in the
treatment of leukaemia was by Lissauer, a German
physician who administered it to a woman with chronic
myeloid leukaemia in 1865. She was temporarily restored to
health for some months (Lissauer, 1865). Arsenic became
the first agent of some beneficial use in the treatment of
certain forms of leukaemia, and in some cases it produced a
short remission. Cutler and Bradford published the results of
their scientific study of the effects of arsenic on blood cells
and found that in leukaemia the white cell count was
reduced but that the red cell count was also reduced
dramatically (Cutler & Bradford, 1878). Dr George Dock
regularly prescribed arsenic solution in the treatment of
leukaemia while at Ann Arbor in the early 1900s and gave
a pragmatic reason for doing so with his belief `that patients
tended to get well, even temporarily, when it was given
287
whereas when other remedies were prescribed they did not'
(Davenport, 1982).
It was not surprising that blood transfusion should be
applied as a treatment as leukaemia was now understood by
physicians to be a disease of the blood. James Blundell,
Professor of Obstetrics at Guy's Hospital, improved the
method of transfusion and stated that it was not necessary
to replace all the blood lost; a smaller quantity of transfused
blood was adequate and, for humans, only human blood
should be used (Blundell, 1828). The first case of transfusion of the blood of a patient with leukaemia was carried out
by Callender in 1873 at St. Bartholomew's Hospital in
London (BMJ Editorial, 1873). The transfusion provided
short relief for the patient, a matter of some 6 weeks. The
second transfusion was on a girl with a severe form of
purpuria who was a patient of Dr Charles West, physician
and founder of The Hospital for Sick Children, Great
Ormond Street. This transfusion `terminated fatally', most
probably because the haemorrhage had already reached a
life-threatening stage. The problem of clotting of the blood
often thwarted successful transfer from donor to recipient,
and it was not until 1900 that the most important advance
towards safe and effective transfusion took place with the
discovery by Karl Landsteiner of the human blood groups
(Landsteiner, 1901).
The discovery of X-rays in 1895 by Wilhelm RoÈntgen
brought a new treatment for leukaemia, with initial
temporary results similar to those produced by arsenic.
Differing views were formed on the development and
efficacy of X-rays in their use in leukaemia and on whether
too much had been expected of the new therapy. William
Osler commented in 1914 that he had not seen any striking
permanent improvement in patients treated with X-rays and
the realization came that X-rays did not cure leukaemia,
even in cases that responded well initially. In some cases,
there was no response at all. The assessment of the value of
X-rays continued for 30 years. The survey by Minot et al
(1924), which provided a comprehensive and informative
report on the nature and clinical evaluation of chronic
myeloid leukaemia (the most common form of leukaemia
seen in the last century), showed that at that time X-ray
therapy was best used on patients with chronic leukaemias
and some lymphomas, but all acute leukaemias and a
proportion of the lymphomas proved resistant to treatment.
Early epidemiology
One of the first epidemiology studies on leukaemia was
published in 1879 by W. R. Gowers (later Sir William)
(Gowers, 1879). It covered 154 cases and was based
principally on social data of cases. At this time, the disease
was thought to be a chronic condition. Gowers and others
offered some speculative aetiological comments including
exposure to malaria, which was then present in some areas
of Britain. A survey of 20 cases indexed as leukaemia in the
register at Guy's Hospital in the period 1889±94 showed on
review that 40% were doubtful. Although Friedreich
suggested that his patient in 1857 had an acute form of
leukaemia, it was not until the close of the nineteenth
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century that a small number of cases were reported in
Europe of an acute form of the disease.
A focal point was Obrastzow's report (Obrastzow, 1890)
of two cases of acute leukaemia in Kiev in l889, where there
was strong evidence of the transfer of the disease from a
patient to a male nurse within the hospital; in both cases,
there was a duration of diagnosis to death of just 17 d.
Attention on acute leukaemia was focused particularly in
America. Cabot, a Boston physician, published a series of 34
acute cases to l893 with an average duration of 4.5 weeks
and a maximum survival of 9 weeks (Cabot, 1894).
Fraenkel (1895) reported an extensive reÂsume of 10 cases
of acute leukaemia, drawing attention to the histological
characteristics of the blood cells. Churchill, a Chicago
physician, in a collection of 15 cases of the acute form of the
disease gathered from various sources showed that the
duration of leukaemia in children was short, ranging from
days to 5 months with an age range from the newborn to
10 years (Churchill, 1904). Buchanan, a Liverpool physician and pathologist, provided detailed clinical descriptions
of both acute myeloid and lymphoblastic leukaemia, the
onset of each of which he described as being insidious,
rapid and progressive (Buchanan, 1909). The popular
view then was that acute leukaemia was either infectious
or contagious in nature. The number of cases was
small, which indicated that if acute leukaemia was an
infectious or contagious disease it was not presenting in the
traditional pattern or quantity of the common infectious
diseases.
The infective theory of acute leukaemia was discussed in
1917 by Gordon Ward, who had collected a series of 1457
cases of leukaemia of all types. This was the first reliable
epidemiological survey (Ward, 1917). This remarkable
work, produced when Ward was on war service with the
Royal Army Medical Corps (RAMC), discussed the infective
theory of acute leukaemia: leukaemia in pregnancy, familial
cases and whether it was a congenital disease. He drew up
incidence tables for the various types of leukaemia, sex
distribution and duration of illness, all of which were
noticeably close to our current understanding. Ward can be
credited with the identification of acute leukaemia as a
disease which mostly affects children and which peaks in
the 0±5 years age group. There was little evidence to
suggest, he wrote, that it was by nature infectious or
hereditary (Fig 5). His work was received as an authoritative reference by such leading physicians as Minot,
Whitby, Britton and Wintrobe.
The irregular pattern of leukaemia morbidity was
evidenced by the clustering of cases occurring in specific
areas within a short period of time. The first report of a
cluster came from Paris with four adult cases occurring in
close proximity to the HoÃpital St. Louis, all supportive of a
diagnosis of acute myeloid leukaemia (Aubertin & Bosviel,
1923). From 1930 onwards, there was a noticeable increase
in the number of cases of leukaemia, and this raised the
question of whether the incidence of the disease was
increasing. Undoubtedly, the introduction of a number of
new instruments to speed the process of counting blood cells
and to improve the accuracy of haemoglobinometry was an
Fig 5. The age incidence of the three varieties of leukaemia
arranged in 5-yearly periods (Ward, 1917).
aid to diagnosis. The technique of sternal marrow aspiration
was first described by Mikhail Arinkin of Leningrad in 1927,
and in 1933 R. P. Custer developed the biopsy examination
of the bone marrow as a new diagnostic procedure.
Intractability of leukaemia
At this time, pernicious anaemia was regarded equally with
leukaemia as a fatal disease. Understandably, after the
revolution in the treatment of pernicious anaemia and the
revelation of its aetiology following the work of Whipple,
Minot, Murphy and Castle in discovering a simple cure in
liver extract (the intrinsic factor being discovered later to be
vitamin Bl2), there was an increasing sense of frustration
with the unyielding disease of leukaemia. This depression
was expressed by Forkner in 1938. He wrote, `It is well
known that acute leukaemia is rarely benefited by treatment
of any sort'. And Wintrobe in 1945 stated, `There is no
specific treatment for leukaemia'. The first complete
exchange blood transfusion, born of desperation, was
carried out by Bessis and Bernard in 1947 and achieved a
q 2001 Blackwell Science Ltd, British Journal of Haematology 112: 282±292
Historical Review
remission which lasted a few months. At that time,
remission was almost unknown in acute leukaemia.
Professor Bruce Wiseman, chairman of the Department of
Medicine of Ohio State University, summed up the position
in 1948 by stating that the problem presented by leukaemia
was more important than any other in the field of
haematology and he suggested in a wry understatement
that `a fresh if not new point of view with respect to this
disease would not be undesirable'. The new points of view
had their origins in the use of mustard gas, a poisonous
chemical warfare agent used by the German forces in World
War I. During the Second World War, the Allies believed
that repeat use of mustard gas was a possibility so
preventive measures were taken, including secret research
on nitrogen mustards, the chemical analogues of the gas. It
was found that they produced marked changes in the
haemopoietic system and especially in depressing the blood
cells causing leucopenia, thrombopenia and anaemia, the
rate of change being determined by the levels of concentrated exposure. It was soon realized that nitrogen mustard
(then known by the code name HN2) produced an action on
blood cells and the bone marrow unlike any other known
chemical substance.
The advent of chemotherapy
With the entry of the United States into World War II
in 1941, military secrets were immediately exchanged.
Cornelius P. Rhoads, head of the medical division of the US
Chemical Warfare Service, recruited many investigators
who, once discharged from their military duties, became a
formidable group of leaders in the early development of
chemotherapy applied to the treatment of neoplastic
diseases. The first clinical observations in America on
nitrogen mustard were made in 1942 by Gilman and
Philips, but because of wartime restrictions on classified
information they were not published until 4 years later.
While working on the pharmacology of certain nitrogen
mustard derivatives, they noted the effects of these
compounds on lymphoid tissues (Gilman & Philips, 1946).
This led to studies on experimental neoplasms and subsequently to clinical trials at Yale University, which showed
that methyl-bis-(b-chloroethyl) amine had significant activity against Hodgkin's disease and for certain cases of
lymphosarcoma (reviewed in Gilman & Philips, 1946).
Three further publications appeared in the same year
(Rhoads, 1946; Goodman et al, 1946; Jacobson et al,
1946) with mixed results, showing temporary benefit in
cases of Hodgkin's disease, lymphosarcoma and chronic
leukaemias. The results were similar to those obtained with
radiotherapy. The opening of the Sloan Kettering Institute in
1948, closely tied to the Memorial Hospital in New York,
included an Experimental and Clinical Chemotherapy
Division staffed by C. C. Stock, D. Karnofsky, F. Philips, J.
H. Burchenal and their associates. Other centres involved
included Boston, Chicago and Salt Lake City.
During the same period in Britain, John Wilkinson,
Director of the Department of Haematology, Manchester
Royal Infirmary, had been involved in work on nitrogen
mustards with F. Fletcher since 1942, but they too were
289
unable to publish their findings until 1947. They reported
on 18 cases of leukaemia, Hodgkin's disease and
polycythaemia vera treated with b-chloroeth-lyamine
hydrochlorites (Wilkinson & Fletcher, 1947) with results
similar to those obtained in the USA.
The early pioneers of chemotherapy were not discouraged
by the initial results of this new challenge in what was
essentially experimental medicine. There was no other
effective therapy. The surprising result of their efforts was
that the most beneficial clinical effect occurred in the
lymphomas rather than the leukaemias, and some patients
who had become resistant to X-ray therapy responded to
nitrogen mustard treatment. The first results were put into
perspective by Gilman and Philips's concluding remarks in
their classic summary in 1946 of the wartime work by
themselves and others (Gilman & Philips, 1946). They
stated that at present only two of the nitrogen mustards had
been investigated clinically and that `literally hundreds of
congeners remained to be synthesized and evaluated'. This
was followed by intensive work by investigators in Britain
and the USA to find preparations with a targeted effect on
abnormal cells which were less toxic and capable of oral
administration.
In Britain, Sir Alexander Haddow formed a group with his
associates Eric Boyland, Walter Ross, George Timmin and
David Galton at the Chester Beatty Research Institute
in London to study the growth-promoting and growthinhibitory properties of many chemicals, mostly synthesized
by the chemists in the team. Knowing the many clinical
disadvantages of nitrogen mustard, they became especially
interested in alkylating agents and hoped that chemical
manipulations might improve the therapeutic efficacy.
This resulted in the development of busulphan (Myleran),
which became the mainstay of the treatment of chronic
granulocytic leukaemia, and chlorambucil, melphalan
and Urethane. Clinical collaboration resulted in encouragement and tremendous support in the early days, which
Galton recalls as being exciting, stimulating, frustrating and
always challenging. Internationally, there were close links
with the Sloan Kettering staff and with other American
centres.
It was known in 1943 that folic acid, a vitamin in the B
group, was important in haemopoiesis (Pfiffner et al, 1943;
Stokstad, 1943) and that some preparations containing folic
acid inhibited the growth of experimentally induced
tumours in mice and rats (Lewisohn et al, 1944). Others
claimed that folic acid might stimulate the growth of
leukaemic cells. Although it was shown later that much
of this work was flawed, it did stir interest in the use of
antimetabolites and it was a group led by Y. SubbaRow
in the Research Division of the Lederle Laboratories of
the American Cyanamid Company who synthesized the
first folic acid antagonists and offered them for clinical
trial. The first clinical trials reported from Lederle were
effective and encouraged further research (SubbaRow et al,
1946).
The effectiveness of the folic acid antagonists ± pteroylaspartic acid and methylpteroic acid in the first trial ± was
improved upon by Franklin and colleagues, who reported
q 2001 Blackwell Science Ltd, British Journal of Haematology 112: 282±292
290
Historical Review
from the Lederle Laboratories that the folic acid antagonist
`accelerated' pteroylglutamic acid deficiency in mice and
chickens (Franklin et al, 1947). The development of these
folic acid conjugates led to the synthetic compound 4aminopteroylglutamic acid, which was named aminopterin.
Sidney Farber, who was appointed Pathologist in Chief at
the Harvard Medical School in l947, recognized from the
experience that he had gained on folic acid through his
relationship with SubbaRow that folic acid antagonists
might be of value in the treatment of children with acute
leukaemia. Farber was right. The clinical trials conducted in
1947 and 1948 on l6 infants and children with acute
leukaemia to whom aminopterin was administered by
intramuscular injection resulted in 10 patients achieving
clinical, haematological and pathological evidence of major
improvement, but this was temporary (Farber et al, 1948).
The Boston group led by Farber had demonstrated for the
first time that it was possible to obtain temporary remission
in patients with acute leukaemia. Both Heinle & Welch
(1948) and Farber (1949) noted that a deficiency of folic
acid deters haematopoiesis. This offered a new direction for
further research concerning the nature and treatment of
acute leukaemia. The findings of Farber and colleagues were
soon confirmed by other clinicians. John Dacie obtained
temporary remissions in 9 out of 13 patients, Dameshek
gained remissions in 9 out of 35 patients and Wilkinson in 6
out of 21 patients. Aminopterin was subsequently to be
replaced by methotrexate. The therapeutic value of the
adrenal corticosteroids was discovered in 1949 (Farber et al,
1950; Pearson et al, 1949), of which prednisone became
the most widely used. These became especially useful for
the induction of remissions in children with acute
leukaemia and, to a lesser extent, in adults. Shortly after,
6-mercaptopurine was discovered (Elion et al, 1951, 1952).
This pioneering work in the therapy of leukaemia became a
motivating and energizing force. It was the start of a success
story that is continually progressing in answer to Virchow's
words of 1858, `I do not wish by any means to infer that the
disease in question [leukaemia] is incurable; I hope on the
contrary that for it too remedies will at length be discovered'
(Virchow, 1858).
Hon. Fellow, Institute of Child Health, Gordon J. Piller
University of London, Hon. Research
Fellow, University of Leeds,
Abbotswold, Great Wolford, Shipston on
Stour, Warwickshire CV36 5NQ, UK
ACKNOWLEDGMENTS
I am indebted to Professor Sir John Dacie, Professor John
Goldman and the late Professor Roger Hardisty for their
expert opinions given on all the early cases of leukaemia.
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Keywords: leukaemia, history of medicine, blood disorders,
early chemotherapy, epidemiology.
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